Drug delivery system and methods of use

ABSTRACT

Electrospun fibers are utilized to improve the mechanical characteristics of a contact lens reducing the weight and mechanical strength of the polymers from which the lenses are typically formed. Electrospun fibers are also utilized as a drug delivery system, both through direct use in the eye and by inclusion of the fibers in a contact lens. The fibers are loaded with therapeutic drugs by a variety of methods and processed by coating and cross-linking the fibers.

CROSS-REFERENCE TO RELATED APPLICATIONS

This non-provisional application claims priority of U.S. ProvisionalPatent Application No. 61/125,985 filed on Apr. 29, 2008, whichapplication is incorporated herein by reference.

BACKGROUND Field of the Invention

Electrospun polymer fibers provide a material with a variety offavorable characteristics that may be tailored to fit variousapplications. The fibers in the electrospun materials provide superiormechanical strength with reduced weight and volume. They also have highsurface area and porosity which may be altered as desired duringfabrication.

It is therefore desirable to provide a drug delivery system utilizingelectrospun polymer fibers. The drug delivery system may utilize thefibers for insertion directly into the eye maintaining the concentrationof the drug in the eye at an efficacious level throughout the period ofdrug delivery.

The system may also utilize an improved contact lens incorporatingelectrospun fibers with desired characteristics, and a system and methodfor delivering ophthalmic drugs from the improved contact lens to an eyeover an extended period of time while maintaining the concentration ofthe drug in the eye at an efficacious level throughout the period ofdrug delivery.

It is also desirable to provide a system and method for preloading drugsin the delivery system in a manner that allows the delivery system to bestored for an extended period of time.

SUMMARY OF THE INVENTION

The drug delivery system described herein utilizes both “raw”electrospun fibers and an improved contact lens as the means of drugdelivery. The fibers and the improved contact lens provide a drugdelivery system comprising a drug-releasing scaffold formed from a matof electrospun fibers and methods for incorporating various therapeuticdrugs into the mat. The fiber mat may be utilized directly in the eyefor delivery of drugs, or incorporated into an improved contact lens.

The therapeutic drugs may be loaded into the drug delivery system bysoaking the electrospun mats in a solution containing the drug, or byproviding the drugs in the solution feeding the electrospinning processthus incorporating the drug into the fibers in the electrospun mat.Various processes for treating the electrospun mats after loading withtherapeutic drugs are also described for improving the drug deliverycharacteristics, such as coating the mats in a polymer and cross-linkingthe electrospun fibers.

The improved contact lens described herein also comprises a contact lensthat incorporates electrospun fibers to provide desirable physicalcharacteristics. The improved contact lens may be fabricated with athinner cross-section due to the increased mechanical strength andrigidity of the electrospun fiber materials. The thinner cross-sectionlens provides increased oxygen permeability while maintaining mechanicalstrength.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a scanning electron micrograph of a mat of fibers formed byelectrospinning poly(vinyl)alcohol.

FIG. 2 is a scanning electron micrograph of a mat of fibers formed byelectrospinning poly(vinyl)alcohol and crosslinked by submersion inmethanol.

FIG. 3 is a scanning electron micrograph of a mat of fibers formed byelectrospinning poly(vinyl)alcohol, crosslinked by submersion inmethanol, coated with an aqueous solution of poly(vinyl)alcohol, andthen crosslinked a second time.

FIG. 4 is a graph of the concentration of a therapeutic drug released bya fiber mat soak-loaded with the therapeutic drug after deposition.

FIG. 5 is a graph of the concentration of a therapeutic drug released bya fiber mat fabricated from a precursor solution containing thetherapeutic drug and coated with poly(vinyl)alcohol.

FIG. 5A is a graph of the first 60 minutes of the time period shown inFIG. 5.

FIG. 6 is a graph of the concentration of a therapeutic drug released bya fiber mat fabricated from a precursor solution containing thetherapeutic drug coated with poly(vinyl)alcohol, and crosslinked withmethanol.

FIG. 6A is a graph of the first 60 minutes of the time period shown inFIG. 6.

DETAILED DESCRIPTION

Electrospun Fiber Mat Fabrication

The electrospun fiber mat used in the present invention is fabricated bypolymerizing electrospun fibers and loading a therapeutic drug in thefiber mat using a variety of techniques, which are described below withexamples.

The electrospinning process typically comprises an apparatus includingone or more electrically-conducting liquid dispenser, such as astainless steel needle, disposed adjacent to a collector. The liquiddispenser is held at a high electric potential, or voltage, with respectto the collector. The electric potential may be either alternatingcurrent (AC) or direct current (DC), or a DC biased AC voltage.Alternatively, a substrate for receiving the electrospun fibers may beinserted between the conducting dispenser and the collector such thatthe fibers will be deposited on the substrate as they are propelled fromthe liquid dispenser by the electric field toward the collector.

A solution source, or well, containing a solution of the polymer andvarious other components which may include a polymer precursor (monomer)is attached to the electrically-conducting liquid dispenser by a fluidconducting element such as a short tube. The polymer solution ispropelled through the dispenser at a predetermined rate, either bygravity or by mechanical means such as a pump. As the solution isdispensed through the electrically-conducting dispenser, the highelectric potential between the dispenser and the collector leads to theformation of uniform fibers which are deposited on the collector. Thefibers may be micro-fibers or nano-fibers depending on the parameters ofthe electrospinning process. As the fibers are deposited on thecollector they overlap to form a mat, as further described below.

Polymer solutions for use in the fiber mat fabrication disclosed hereininclude, but are not limited to, aqueous solutions having between 5 and15 percent polymer by weight. Various additives may be added to theprecursor solution to lower surface tension, or to otherwise alter thecharacteristics of the solution or the electrospun fibers as desired.For example, surfactants, such as Triton X-100, poloxomer 407 or othersuitable surfactant, may be added to the precursor solution to lower thesurface tension of the solution.

Polymers for use in the electrospinning process include, but are notlimited to the following: poly(2-hyroxyethylmethacrylate) (pHEMA),poly(acrylic acid) (PAA), poly(methacrylic acid), poly(Vinyl pyrolidone)(PVP), poly(N-vinyl pyrolidone) (PVP), Polyvinyl alcohol (PVA),poly(methyl methacylate) (PMMA), poly(glyceral methacrylate) (PGMA),Silicone Hydrogels, Fluorocarbon hydrogels, polyacrylamide (PAM),Silicone and 3-methacryloxy-2hydroxypropyloxy)propylbis(trimethylsiloxy)methylsilane. Other polymersmay be utilized if soluble in a solvent such as water, methanol,ethanol, hexane, acetonitrile, or tetrahydrofuran to allow theelectrospinning process. If the fibers are to be utilized in a contactlens as described below, the fibers are preferably formed from a polymerthat is the same as the polymer to be used in the remainder of thecontact lens, or a polymer that has a similar index of refraction, toreduce negative optical characteristics of the improved contact lens.Additional polymer precursor solutions are described below.

As the fibers are deposited on the collector they form a mat ofoverlaying fibers. In some methods of depositing the fibers, thecollector is translated in one or more linear dimensions, or in arotational or orbital manner, perpendicular to the direction of fiberdeposition to increase the area over which the fibers are deposited andto improve the consistency of the fiber mat.

After a desired period of deposition, a fiber mat of a certain thicknesswill be formed, and can be removed from the electrospinning apparatusand prepared for further processing.

After deposition, the fiber mat may be processed in several ways toimprove the characteristics of the fiber mat. The fiber mat may becoated with a polymer by exposing the mat to an solution of polymerprecursor. As described below, coating the fiber mat alters thecharacteristics of the fiber mat, including the release of drugsincorporated in the fiber mat. After any chemical processing, the matsmay be further processed by cutting into sections or grinding intoparticles.

The fiber mats may also be processed by exposing them to a crosslinkingagent such as ethylene glycol dimethacrylate (EGDMA), tetraetheyleneglycol dimethacrylate (TEGDMA), divinyl benzene (DVB), divinylacrylamide(DVACR), or any tri-allyl crosslinking agent. Methanol may be added toPVA to crosslink the polymer. The crosslinking process increases themechanical stability of the fiber mat by linking adjacent fibers as theyintersect randomly in the fiber mat.

An example process for creating an electrospun fiber mat is as follows.

-   -   1. Combine the following materials, mix, place over heat and        stir inside round-bottom flask with attached condenser for 6.5        hours.        -   10 wt % PPVA+2 wt % Triton X-100+DI water        -   11.363 g Polyvinyl alcohol (Sigma-Aldrich 99% hydrolyzed)        -   2.277 g Triton X-100 (Aldrich)        -   27.539 g Ultra high purified water added to Triton X-100            (Elgan)        -   72.459 g Ultra high purified water added to PVA (Elgan).

This is the PVA polymer mixture. Without allowing the polymer mixture tocool performing the following steps.

-   -   2. Add 2.000 ml of Vigamox to 14.141 g of the PVA polymer        mixture and vortex stir for 1 minute.    -   3. Add 7.0 ml of the PVA/Vigamox solution to 2 syringes for a        total of 14.0 ml of solution.    -   4. Electrospin the PVA/Vigamox solution from both needles        simultaneously at the following parameters:        -   Dispense rate: 1.8 ml/hr        -   18 gauge blunt end needles        -   Voltage: 30 kV        -   Travel distance: 4 in        -   Total time: 2.5 hours    -   5. After electrospinning, the resulting mat is cut into        approximately 3.0 mg squares.    -   6. If crosslinking is desired, soak the squares in methanol for        7 hours and allow to air dry in ambient conditions overnight.    -   7. Coat the squares in the remaining PVA polymer solution        created in step 1 above. Before coating the squares, the PVA        polymer solution is heated in a round bottom flask with attached        condenser for 2 hours.    -   8. After coating the squares in the polymer solution, allow them        to air dry in ambient conditions overnight.    -   9. If a second cross-link is desired soak the squares in        methanol for 7 hours and then allow them to air dry in ambient        conditions overnight.

When measuring drug release profiles the following procedure wasutilized:

-   -   1. Each sample mat was placed into 0.5 ml ISO 18369 saline        solution in cuvettes.    -   2. Absorbance measurements were taken at 1, 5, 10, 20, 60, 1440,        and 2880 minutes by removing the sample mat with tweezers and        measuring the absorbance at 336 nm. Sample mats were immediately        placed back in the sample cuvette after measurement.    -   3. Measurements were normalized by mass of the sample mat prior        to dip-coating.        Polymer Materials for Electrospun Fibers

Suitable hydrophobic comonomers (a) for use in electrospun fibersinclude, without this list being exhaustive, C₁-C₁₈alkyl andC₃-C₁₈cycloalkyl acrylates and methacrylates, C₃-C₁₈alkylacrylamides and-methacrylamides, acrylonitrile, methacrylonitrile, vinylC₁-C₁₈alkanoates, C₂-C₁₈alkenes, C₂-C₁₈haloalkenes, styrene, lower alkylstyrene, lower alkyl vinyl ethers, C₂-C₁₀perfluoroalkyl acrylates andmethacrylates or correspondingly partly fluorinated acrylates andmethacrylates, C₃-C₁₂perfluoroalkyl-ethyl-thiocarbonylaminoethylacrylates and methacrylates, acryloxy- and methacryloxy-alkylsiloxanes,N-vinylcarbazole and C₁-C₁₂alkyl esters of maleic acid, fumaric acid,itaconic acid, mesaconic acid and the like. Preferred comonomers are,for example, acrylonitrile, C₁-C₄alkyl esters of vinylically unsaturatedcarboxylic acids having 3 to 5 carbon atoms, or vinyl esters ofcarboxylic acids having up to 5 carbon atoms.

Examples of suitable hydrophobic comonomers (a) include methyl acrylate,ethyl acrylate, propyl acrylate, isopropyl acrylate, isobutyl acrylate(IBA), isooctyl acrylate (OA), isodecyl acrylate (DA), cyclohexylacrylate, 2-ethylhexyl acrylate (EHA), methyl methacrylate, ethylmethacry-late, propyl methacrylate, butyl acrylate, vinyl acetate, vinylpropionate, vinyl butyrate, vinyl valerate, styrene, chloroprene, vinylchloride, vinylidene chloride, acrylonitrile, I-butene, butadiene,methacrylonitrile, vinyl toluene, vinyl ethyl ether,perfluorohexylethylthiocarbonylaminoethyl methacrylate, isobomylmethacrylate, trifluoroethyl methacrylate, hexafluoroisopropylmethacrylate, hexafluorobutyl(meth)acrylate (HFBMA and HFBA),tris-trimethylsilyloxy-silyl-propyl methacrylate (TRIS),3-methacryloxypropylpentamethyldisiloxane andbis(methacryloxypropyl)tetramethyldisiloxane. Preferred examples ofhydrophobic comonomers (a) are methyl methacrylate, IBA, HFBA, HFBMA,OA, EHA, DA, TRIS and acrylonitrile. Suitable hydrophilic comonomers (a)include, without this list being conclusive, hydroxyl-substituted loweralkyl acrylates and methacrylates, acrylamide, methacrylamide, loweralkylacrylamides and -methacrylamides, ethoxylated acrylates andmethacrylates, hydroxyl-substituted lower alkylacrylamides and-methacrylamides, hydroxyl-substituted lower alkyl vinyl ethers, sodiumvinylsulfonate, sodium styrenesulfonate,2-acrylamido-2-methylpropanesulfonic acid, N-vinylpyrrole,N-vinyl-2-pyrrolidone, 2-vinyloxazoline,2-vinyl-4,4′-dialkyloxazolin-5-one, 2- and 4-vinylpyridine, vinylicallyunsaturated carboxylic acids having a total of 3 to 5 carbon atoms,amino-lower alkyl (where the term “amino” also includes quaternaryannnonium), mono-lower alkylamino-lower alkyl and di-loweralkylamino-lower alkyl acrylates and methacrylates, allyl alcohol andthe like. Preferred comonomers are, for example, N-vinyl-2-pyrrolidone,acrylamide, methacrylamide, hydroxyl-substituted lower alkyl acrylatesand methacrylates, hydroxyl-substituted lower alkylacrylamides and-methacrylamides and vinyli-cally unsaturated carboxylic acids having atotal of 3 to 5 carbon atoms. Examples of suitable hydrophiliccomonomers (a) include hydroxyethyl methacrylate (HEMA), hydroxyethylacrylate, hydroxypropyl acrylate, trimethylammonium-2-hydrox-ypropylmethacrylate hydrochloride (Blemer®QA, for example from Nippon Oil),dimethylaminoethyl meth acrylate (DMAEMA), dimethylaminoethylmethacrylamide, acrylamide, methacrylamide, N,N-dimethylacrylamide(DMA), allyl alcohol, vinylpyridine, glycerol methacrylate,N-(1,I-dimethyl-3-oxobutyl)acrylamide, N-vinyl-2-pyrrolidone (NVP),acrylic acid, methacrylic acid and the like. Preferred hydrophiliccomonomers (a) are 2-hydroxyethyl methacrylate, dimethylaminoethylmethacrylate, trimethylammonium-2-hydroxypropyl methacrylatehydrochloride, N,N-dimethylacrylamide and N-vinyl-2-pyrrolidone.

The polymers according to the invention are built up in a known mannerfrom the corresponding monomers (the term monomers here also including amacromer according to the invention) by a polymerization reaction withwhich the expert is familiar. Usually, a mixture of the abovementionedmonomers is heated, with the addition of an agent which forms freeradicals. Such an agent which forms free radicals is, for example,azoisobutyronitrile (AIBN), potassium peroxodisulfate, dibenzoylperoxide, hydrogen peroxide or sodium percarbonate. If the compoundsmentioned are heated, for example, free radicals are then formed, byhomolysis, and can then, for example, initiate a polymerization.

A polymerization reaction can be carried out using a photoinitiator.Photopolymerization is the term used in this case. Forphotopolymerization, a photoinitiator which can initiate free radicalpolymerization and/or crosslinking by the use of light is suitablyadded. Examples of this are familiar to the expert, and specifically,suitable photoinitiators are benzoin methyl ether, I-hydroxycyclohexylphenyl ketone and Darocur and Irgacur types, preferably Darocur 11738®and Darocur 29590®. Reactive photoinitiators which can be incorporated,for example, into a macromer or can be used as a special comonomer (a)are also suitable. Examples of these are to be found in EP 632 329. Thephotopolymerization can then be triggered off by actinic radiation, forexample light, in particular UV light of a suitable wavelength. Thespectral requirements can be controlled accordingly, if appropriate, byaddition of suitable photosensitizers. Polymerization can be carried outin the presence or absence of a solvent. Suitable solvents are inprinciple all solvents which dissolve the monomers used, for examplewater, alcohols, such as lower alkanols, for example ethanol ormethanol, and furthermore carboxylic acid amides, such asdimethylformamide, dipolar aprotic solvents, such as dimethyl sulfoxideor methyl ethyl ketone, ketones, for example acteone or cyclohexanone,hydrocarbons, for example toluene, ethers, for example THF,dimethoxyethane or dioxane, and halogenated hydrocarbons, for exampletrichloroethane, and also mixtures of suitable solvents, for examplemixtures of water with an alcohol, for example a water/ethanol or awater/methanol mixture.

If appropriate, a polymer network can be intensified by addition of aso-called crosslinking agent, for example a polyunsaturated comonomer(b). The invention furthermore relates to a polymer comprising thepolymerization product of a macromer according to the invention with, ifappropriate, at least one vinylic comonomer (a) and with at least onecomonomer (b). Examples of typical comonomers (b) are, for example,allyl(meth)acrylate, lower alkylene glycol di(meth)acrylate, poly loweralkylene glycol di(meth)acrylate, lower alkylene di(meth)acrylate,divinyl ether, divinyl sulfone, di- or trivinylbenzene,trimethylolpropane tri(meth)acrylate, pentaerythritoltetra(meth)acrylate, bisphenol A di(meth)acrylate,methylenebis(meth)acrylamide, triallyl phthalate or diallyl phthalate

EXAMPLES

Monomer/Cat/Crosslinker % % % % % % MMA 25.5 24.2 GMA 68 HEMA 93.25 9050 NVP VP 92.7 MAA 70 42 TEDGMA .5 .75 EDGMA 1 1 1 1 IPP .2 .2 AIBN .25.3 .3 .25 PVA Fibers 5.3 7.25 PHEMA Fibers 5.25 5 8.75 PVP Fibers 5 *IPPIsopropyl percarbonate *AIBN azoisobutyronitrile

In each example above, electrospun fibers are made by dissolving 15% ofthe polymer in methanol and electrospinning the fibers as describedpreviously. The weight of electrospun fiber is placed in a button mold,monomer composition from the table added, vacuum pulled on the solution,button mold top added, and polymerized at 60° C. in an oven for 24 hoursfollowed by curing at 80° C. for 4 hours. The button removed and lensmachined from the buttons by measuring hydration parameters on thepolymerized materials.

Drug Delivery System Utilizing Electrospun Fibers

The electrospun fibers may be loaded with a therapeutic drug andutilized as a drug delivery system. The fibers can be used as inserts inthe eye, either separately or as a mat. The insert can be placed in thecul-de-sac of the eye in the form of dry fibers or a mat of dry fibers.This dry mat placed in the eye will hydrate thereby releasing thetherapeutic drug as the mat hydrates. The fibers can also be insertedunder the conjunctiva or sclera and will slowly erode away releasing thetherapeutic drug, provided the fiber is not a crosslinked polymericmaterial.

The fiber mats may be stored dry, as noted above, which will minimizethe loss of the therapeutic drug during storage. This will require thatresidual impurities such as monomers be kept to a minimum and thathydration time will be short. The fiber mats may also be stored in wateror another solvent, which will remove impurities from the fiber mats.The storage solution must also contain a sufficient concentration of thetherapeutic drug to prevent the drug from dissolving from the fiberswhile in storage.

This drug delivery system provides for the release of ophthalmic drugsfrom the fiber mat to an eye over an extended period of time, thusimproving the efficacy of the drug by maintaining a therapeuticconcentration of the drug in the eye for a long period of time. Knownmethods of delivering drugs to an eye typically result in initially highconcentrations of drugs that quickly drop to levels which are too lowfor optimal efficacy. The electrospun fibers in the drug delivery systemmay be loaded with appropriate drugs via several methods describedbelow.

In a first method of loading the drug delivery system with appropriatedrugs, the drugs are mixed with the polymer solution in the liquid wellthat feeds the electrospinning process. The drugs are then dispensedwith the polymer solution through the electrically-conducting liquiddispenser, and incorporated directly into the fibers created by theelectrospinning process.

Polymer solutions for use in the drug delivery system include, but arenot limited to, aqueous solutions having between 5 and 15 percentpolymer by weight, similar to the base polymer solution utilized in thecreation of the improved contact lens, with the addition of thetherapeutic drug to be dispensed from the contact lens. Theconcentration of the drug in the contact lens and the rate of release inthe eye are adjusted by altering the concentration of the drug in thepolymer solution. More than one therapeutic drug may be added to thepolymer solution to provide an improved contact lens that delivers a“cocktail” of drugs to the eye which may be tailored as necessary forthe patient.

As an example of fiber mat formation, without limiting the range ofparameters, mats for use with the drug delivery system described hereinmay be created by electrospinning PVA onto a flat rotating collector for4 hours at a dispense rate of 1.8 ml per hour from an 18 gauge stainlesssteel needle situated 4 inches from the collector, and held at 30 kV DCfrom the collector. Varying the electrospinning time, the dispense rate,the needle gauge, the separation between dispenser and collector, andthe dispenser potential are within the scope of the drug delivery systemdescribed herein, and the above described set of parameters is notlimiting of the drug delivery system.

In a second method of loading the drug delivery matrix, the PVA mat iscreated, and then the mat is soaked in a solution containing thetherapeutic drug. In this method, the therapeutic drug must be a watersoluble drug. The amount of drug loaded into the fiber mat is dependent,among other parameters, on the soak time, the rate of uptake of thefibers, the fiber diameter, and the concentration of drug in the soaksolution.

The rate of drug delivery from the fiber mats after placement in the eyeis dependent, among other parameters, on the fiber diameter, the drugsolubility in water, the amount of fiber in the mat (or lens), theamount of drug loaded in the fiber, and other parameters. The rate ofdrug delivery may also be controlled by changing the polymer compositionfrom hydrophilic to hydrophobic, by treating the surface of the fibersto change the diffusion characteristics, by cross-linking the fibers andby coating the fibers with a polymer or other coating.

After the mats are created by electrospinning and subjected todrug-loading processing, if necessary, the mats may be coated with apolymer such as PVA by submersion in an aqueous solution of the polymercoating. They may also be crosslinked before and after the PVA coating.

An example of forming a fiber mat for drug delivery from electrospunfibers loaded with a therapeutic drug comprises the following steps.Dissolve 15% PVA in 5% moxifloxacin to methanol and electrospin intonanofibers. Place spun fibers in methanol containing 0.6% moxifloxacinfor 2 hours and then dry the electrospun fibers. Form the spun fibersinto a matt and store until use as an insert to place dry in the lowercul-de-sac of the eye.

A wide variety of therapeutic drugs may be spun into the fibers, so longas the drug is soluble in a solvent with the polymer solution. Examplesof various types of drugs that may be spun into fibers include thefollowing and any derivatives of the therapeutically-active agents whichmay include, but not be limited to: analogs, salts, esters, amines,amides, alcohols and acids derived from an agent of the invention andmay be used in place of an agent itself.

Examples of the antibacterial antibiotics include, but are not limitedto: aminoglycosides (e.g., amikacin, apramycin, arbekacin, bambermycins,butirosin, dibekacin, dihydrostreptomycin, fortimicin(s), gentamicin,isepamicin, kanamycin, micronomicin, neomycin, neomycin undecylenate,netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin,streptomycin, tobramycin, trospectomycin), amphenicols (e.g.,azidamfenicol, chloramphenicol, florfenicol, thiamphenicol), ansamycins(e.g., rifamide, rifampin, rifamycin sv, rifapentine, rifaximin),.beta.-lactams (e.g., carbacephems (e.g., loracarbef), carbapenems(e.g., biapenem, imipenem, meropenem, panipenem), cephalosporins (e.g.,cefaclor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefazolin,cefcapene pivoxil, cefclidin, cefdinir, cefditoren, cefepime, cefetamet,cefixime, cefinenoxime, cefodizime, cefonicid, cefoperazone, ceforanide,cefotaxime, cefotiam, cefozopran, cefpimizole, cefpiramide, cefpirome,cefpodoxime proxetil, cefprozil, cefroxadine, cefsulodin, ceftazidime,cefteram, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime,cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin,cephaloridine, cephalosporin, cephalothin, cephapirin sodium,cephradine, pivcefalexin), cephamycins (e.g., cefbuperazone,cefmetazole, cefininox, cefotetan, cefoxitin), monobactams (e.g.,aztreonam, carumonam, tigemonam), oxacephems, flomoxef, moxalactam),penicillins (e.g., amdinocillin, amdinocillin pivoxil, amoxicillin,ampicillin, apalcillin, aspoxicillin, azidocillin, azlocillin,bacampicillin, benzylpenicillinic acid, benzylpenicillin sodium,carbenicillin, carindacillin, clometocillin, cloxacillin, cyclacillin,dicloxacillin, epicillin, fenbenicillin, floxacillin, hetacillin,lenampicillin, metampicillin, methicillin sodium, mezlocillin, nafcillinsodium, oxacillin, penamecillin, penethamate hydriodide, penicillin gbenethamine, penicillin g benzathine, penicillin g benzhydrylamine,penicillin g calcium, penicillin g hydrabamine, penicillin g potassium,penicillin g procaine, penicillin n, penicillin o, penicillin v,penicillin v benzathine, penicillin v hydrabamine, penimepicycline,phenethicillin potassium, piperacillin, pivampicillin, propicillin,quinacillin, sulbenicillin, sultamicillin, talampicillin, temocillin,ticarcillin), other (e.g., ritipenem), lincosamides (e.g., clindamycin,lincomycin), macrolides (e.g., azithromycin, carbomycin, clarithromycin,dirithromycin, erythromycin, erythromycin acistrate, erythromycinestolate, erythromycin glucoheptonate, erythromycin lactobionate,erythromycin propionate, erythromycin stearate, josamycin, leucomycins,midecamycins, miokamycin, oleandomycin, primycin, rokitamycin,rosaramicin, roxithromycin, spiramycin, troleandomycin), polypeptides(e.g., amphomycin, bacitracin, capreomycin, colistin, enduracidin,enviomycin, fusafungine, gramicidin s, gramicidin(s), mikamycin,polymyxin, pristinamycin, ristocetin, teicoplanin, thiostrepton,tuberactinomycin, tyrocidine, tyrothricin, vancomycin, viomycin,virginiamycin, zinc bacitracin), tetracyclines (e.g., apicycline,chlortetracycline, clomocycline, demeclocycline, doxycycline,guamecycline, lymecycline, meclocycline, methacycline, minocycline,oxytetracycline, penimepicycline, pipacycline, rolitetracycline,sancycline, tetracycline), and others (e.g., cycloserine, mupirocin,tuberin).

Examples of the synthetic antibacterials include, but are not limitedto: 2,4-diaminopyrimidines (e.g., brodimoprim, tetroxoprim,trimethoprim), nitrofurans (e.g., furaltadone, furazolium chloride,nifuradene, nifuratel, nifurfoline, nifurpirinol, nifurprazine,nifurtoinol, nitrofurantoin), quinolones and analogs (e.g., cinoxacin,ciprofloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin,flumequine, grepafloxacin, lomefloxacin, miloxacin, nadifloxacin,nalidixic acid, norfloxacin, ofloxacin, oxolinic acid, pazufloxacin,pefloxacin, pipemidic acid, piromidic acid, rosoxacin, rufloxacin,sparfloxacin, temafloxacin, tosufloxacin, trovafloxacin), sulfonamides(e.g., acetyl sulfamethoxypyrazine, benzylsulfamide, chloramine-b,chloramine-t, dichloramine t, n.sup.2-formylsulfisomidine,n.sup.4-.beta.-d-glucosylsulfanilamide, mafenide,4′-(methylsulfamoyl)sulfanilanilide, noprylsulfamide,phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine,succinylsulfathiazole, sulfabenzamide, sulfacetamide,sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine,sulfadicramide, sulfadimethoxine, sulfadoxine, sulfaethidole,sulfaguanidine, sulfaguanol, sulfalene, sulfaloxic acid, sulfamerazine,sulfameter, sulfamethazine, sulfamethizole, sulfamethomidine,sulfamethoxazole, sulfamethoxypyridazine, sulfametrole,sulfamidocchrysoidine, sulfamoxole, sulfanilamide,4-sulfanilamidosalicylic acid, n.sup.4-sulfanilylsulfanilamide,sulfanilylurea, n-sulfanilyl-3,4-xylamide, sulfanitran, sulfaperine,sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine,sulfasomizole, sulfasymazine, sulfathiazole, sulfathiourea,sulfatolamide, sulfisomidine, sulfisoxazole) sulfones (e.g., acedapsone,acediasulfone, acetosulfone sodium, dapsone, diathymosulfone,glucosulfone sodium, solasulfone, succisulfone, sulfanilic acid,p-sulfanilylbenzylamine, sulfoxone sodium, thiazolsulfone), and others(e.g., clofoctol, hexedine, methenamine, methenamineanhydromethylene-citrate, methenamine hippurate, methenamine mandelate,methenamine sulfosalicylate, nitroxoline, taurolidine, xibornol).

Examples of the antifungal antibiotics include, but are not limited to:polyenes (e.g., amphotericin b, candicidin, dennostatin, filipin,fungichromin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin,nystatin, pecilocin, perimycin), others (e.g., azaserine, griseofulvin,oligomycins, neomycin undecylenate, pyrroInitrin, siccanin, tubercidin,viridin).

Examples of the synthetic antifungals include, but are not limited to:allylamines (e.g., butenafine, naftifine, terbinafine), imidazoles(e.g., bifonazole, butoconazole, chlordantoin, chlormiidazole,clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole,isoconazole, ketoconazole, lanoconazole, miconazole, omoconazole,oxiconazole nitrate, sertaconazole, sulconazole, tioconazole),thiocarbamates (e.g., tolciclate, tolindate, tolnaftate), triazoles(e.g., fluconazole, itraconazole, saperconazole, terconazole) others(e.g., acrisorcin, amorolfine, biphenamine, bromosalicylchloranilide,buclosamide, calcium propionate, chlorphenesin, ciclopirox, cloxyquin,coparaffinate, diamthazole dihydrochloride, exalamide, flucytosine,halethazole, hexetidine, loflucarban, nifuratel, potassium iodide,propionic acid, pyrithione, salicylanilide, sodium propionate,sulbentine, tenonitrozole, triacetin, ujothion, undecylenic acid, zincpropionate).

Examples of the antineoplastic agents include, but are not limited to:antineoplastc antibiotics and analogs (e.g., aclacinomycins, actinomycinf.sub.1, anthramycin, azaserine, bleomycins, cactinomycin, carubicin,carzinophilin, chromomycins, dactinomycin, daunorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, idarubicin,menogaril, mitomycins, mycophenolic acid, nogalamycin, olivomycines,peplomycin, pirarubicin, plicamycin, porfiromycin, puromycin,streptonigrin, streptozocin, tubercidin, zinostatin, zorubicin),antimetabolites exemplified by folic acid analogs (e.g., denopterin,edatrexate, methotrexate, piritrexim, pteropterin, Tomudex®,trimetrexate), purine analogs (e.g., cladribine, fludarabine,6-mercaptopurine, thiamiprine, thioguanine), pyrimidine analogs (e.g.,ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine,doxifluridine, emitefur, enocitabine, floxuridine, fluorouracil,gemcitabine, tagafur).

Examples of the steroidal anti-inflammatory agents include, but are notlimited to: 21-acetoxypregnenolone, alclometasone, algestone,amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone,clobetasol, clobetasone, clocortolone, cloprednol, corticosterone,cortisone, cortivazol, deflazacort, desonide, desoximetasone,dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone,fluazacort, flucloronide, flumethasone, flunisolide, fluocinoloneacetonide, fluocinonide, fluocortin butyl, fluocortolone,fluorometholone, fluperolone acetate, fluprednidene acetate,fluprednisolone, flurandrenolide, fluticasone propionate, formocortal,halcinonide, halobetasol propionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methylprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylamino-acetate, prednisolone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortol, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, and triamcinolonehexacetonide.

Examples of the non-steroidal anti-inflammatory agents include, but arenot limited to: aminoarylcarboxylic acid derivatives (e.g., enfenamicacid, etofenamate, flufenamic acid, isonixin, meclofenamic acid,mefenamic acid, niflumic acid, talniflumate, terofenamate, tolfenamicacid), arylacetic acid derivatives (e.g., aceclofenac, acemetacin,alclofenac, amfenac, amtolmetin guacil, bufexamac, cinmetacin, clopirac,diclofenac sodium, etodolac, felbinac, fenclozic acid, fentiazac,glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac,metiazinic acid, mofezolac, oxametacine, pirazolac, proglumetacin,sulindac, tiaramide, tolmetin, tropesin, zomepirac), arylbutyric acidderivatives (e.g., bumadizon, butibufen, fenbufen, xenbucin),arylcarboxylic acids (e.g., clidanac, ketorolac, tinoridine),arylpropionic acid derivatives (e.g., alminoprofen, benoxaprofen,bermoprofen, bucloxic acid, carprofen, fenoprofen, flunoxaprofen,flurbiprofen, ibuprofen, ibuproxam, indoprofen, ketoprofen, loxoprofen,naproxen, oxaprozin, piketoprolen, pirprofen, pranoprofen, protizinicacid, suprofen, tiaprofenic acid, ximoprofen, zaltoprofen), pyrazoles(e.g., difenamizole, epirizole), pyrazolones (e.g., apazone,benzpiperylon, feprazone, mofebutazone, morazone, oxyphenbutazone,phenylbutazone, pipebuzone, propyphenazone, ramifenazone, suxibuzone,thiazolinobutazone), salicylic acid derivatives (e.g., acetaminosalol,aspirin, benorylate, bromosaligenin, calcium acetylsalicylate,diflunisal, etersalate, fendosal, gentisic acid, glycol salicylate,imidazole salicylate, lysine acetylsalicylate, mesalamine, morpholinesalicylate, 1-naphthyl salicylate, olsalazine, parsalmide, phenylacetylsalicylate, phenyl salicylate, salacetamide, salicylamide o-aceticacid, salicylsulfuric acid, salsalate, sulfasalazine),thiazinecarboxamides (e.g., ampiroxicam, droxicam, isoxicam, lornoxicam,piroxicam, tenoxicam), E-acetamidocaproic acid, s-adenosylmethionine,3-amino-4-hydroxybutyric acid, amixetrine, bendazac, benzydamine,.alpha.-bisabolol, bucolome, difenpiramide, ditazol, emorfazone,fepradinol, guaiazulene, nabumetone, nimesulide, oxaceprol, paranyline,perisoxal, proquazone, superoxide dismutase, tenidap, and zileuton.

Examples of anti-allergic agents include, but are not limited to:tranilast, ketotifen fumarate, pheniramine, diphenhydraminehydrochloride, sodium cromoglicate, bepotastine, epinastine HCl,olopatadine hydrochloride, levocombstine HCl, and bepotastine besilate.

Examples of glaucoma-treating agents include, but are not limited to:pilocarpine hydrochloride, carbocal, latanoprost, travoprost,bimatoprost, betaxolol, levobunalol, timolol, iganipidine, brinzolamide,brimonidine and isopropylunoprostone.

Examples of antiviral agents include, but are not limited to:idoxuridine, acyclovir, and trifluorouridine.

Examples of anti-mycotic agents include, but are not limited to:pimaricin, fluconazole, miconazole, amphotericin B, flucytosine, anditraconazole.

Formation of the Improved Contact Lens

Once the fiber mats have been produced, they are incorporated into acontact lens as it is manufactured. Acceptable contact lens polymers foruse in the improved contact lens, include, but are not limited topolyHEMA, polyHEMA/MA, polyHEMA/NVP/MMA, polyHEMA/MMA, polyHEMA/GMA,polyHEMA/PC, polyVA, polyHEMA/PVP/MA, polyHEMA/PVA/MA, poly MA/PVP, andpolyHEMA/PVP/MMA, Poly GMA/MMA, polyHEMA/ACR, polyAA/HEMA, polyMMA/AA,polysilicone hydrogel, polyfluorocarbon hydrogel, and collagen. The lenspolymer is preferably a homo or co-polymer of the monomer used to formthe fiber mat.

In one method of fabricating the improved contact lens, the lens isformed individually by curing a monomer composition in a mold topolymerize the composition and create the contact lens. The electrospunfiber mats is cut into appropriately-sized sections or ground intoappropriately-sized particles, and incorporated into the contact lens byinserting the mat section into the mold with the monomer compositionprior to polymerization. The fibers are then polymerized with themonomer composition and is incorporated into the improved contact lens.In a second method of fabricating an improved contact lens, the fibersmay be polymerized into a button or rod of polymer material by insertingthe fibers into the appropriate mold and curing with monomers. Thebutton or rod is then processed by cutting or polishing to produce thefinal improved contact lens.

The improved contact lens has superior physical characteristics as aresult of the addition of the electrospun fibers into the lens. Theimproved contact lens may be fabricated with a thinner cross-section dueto the increased mechanical strength and rigidity of the electrospunfiber materials. The thinner cross-section of the lens providesincreased oxygen permeability while maintaining mechanical strength.

Fibers loaded with therapeutic drugs as described above may be used tomanufacture the improved contact lens. When forming a contact lens usingfibers that have been loaded with a therapeutic drug, the polymerizationconditions and other processing steps must be controlled to preventdegradation of the therapeutic drug.

An example of forming a contact lens from electrospun fibers loaded witha therapeutic drug comprises the following steps. Dissolve 15%polyacrylic acid and 5% tobramycin in methanol and electrospinpolyacrylic acid fibers containing the antibiotic. Place these fibers ina button mold and add acrylic acid monomer, 1% EDGMA and 0.25% AIBN.Heat at 550 C for 24 hours and cure at 850 C for 2 hours. Remove fromthe mold and machine into a contact lens. Extract the residual monomersform the lens by placing in physiological saline containing 0.3%tobramycin for 24 hours. Remove from extract solution, replace withfresh 0.3% tobramycin physiological saline, autoclave at 1230 C andstore until use.

The electrospun fiber mats may be incorporated into a contact lens usingother methods of contact lens fabrication. The previous examples ofcontact lens fabrication are illustrative of current contact lensfabrication techniques and methods of incorporating the fiber mat intothose methods of fabrication. They are not intended to be limiting ofthe present invention.

The desired concentration of therapeutic drug in the target tissuedetermines the amount of drug to be loaded in the improved contact lens.The target tissue concentration can be increased by adding additionalfibers to the contact lens or by increasing the concentration of thetherapeutic drug in the solution from which the fibers are spun.

FIG. 1 is a scanning electron micrograph of a fiber mat created byelectrospinning poly(vinyl alcohol). The fibers are deposited randomlythroughout the mat in various orientations.

FIG. 2 is a scanning electron micrograph of a fiber mat created byelectrospinning poly(vinyl alcohol) and crosslinking the resulting matusing methanol as a crosslinking agent. As can be seen in the figure,the fibers are linked at the intersection of overlapping fibers.

FIG. 3 is a scanning electron micrograph of a fiber mat created byelectrospinning poly(vinyl alcohol) and crosslinking the resulting matusing methanol as a crosslinking agent. The mat has then been coatedwith PVA and crosslinked a second time.

The fiber mats are tested for drug release properties by cutting themats into small pieces and placing a piece into aqueous solution. Theconcentration of the drug in the solution is then measured over time.Since there is no mechanism in the solution for the removal of the drug,the concentration of the drug will increase over time to its maximumvalue. If the concentration remains constant, it indicates that thefiber mat is no longer releasing the drug.

FIG. 4 is a graph of the concentration of a therapeutic drug released bya fiber mat soak-loaded with the therapeutic drug after deposition. Theconcentration of the drug released by the soak-loaded mat reached itsmaximum concentration within 5 minutes of the start of the drug releasetest. This indicates that the soak-loaded fiber mat quickly releases allof the drug that was loaded into the mat.

FIG. 5 is a graph of the concentration of a therapeutic drug released bya fiber mat fabricated from a precursor solution containing thetherapeutic drug and coated with poly(vinyl alcohol). This figure showsthat the concentration reaches its maximum value in the first hour, andthus that the fiber mat releases all the therapeutic drug within thattime period.

FIG. 5A provides detail of the increasing concentration for the firsthour of the test. It can be seen that the concentration increases overtime, approaching its maximum value toward the end of the first hour.

FIG. 6 is a graph of the concentration of a therapeutic drug released bya fiber mat fabricated from a polymer solution containing thetherapeutic drug, coated with poly(vinyl alcohol), and crosslinked withmethanol. This figure shows an increasing concentration throughout thetime period of the test, revealing that the fiber mat in this test hascontinued to release the drug throughout the test period. The finalmaximum concentration is in the same range as for the mats shown in FIG.5, however the drug was released over a much longer period of time.

FIG. 6A shows the detail of the initial 60 minutes of the test. Thisperiod of data indicates that the concentration initially quickly jumpsand then begins a more steady increase over time, indicating that thefiber mat initially releases the drug quickly and then slows its rate ofrelease over time.

1. A method for forming a contact lens comprising the steps of:electrospinning a mat of polymer fibers; applying a cross-linkingtreatment to the mat of polymer fibers with a cross-linking agent;coating the mat of polymer fibers with a polymer coating; andincorporating the mat of polymer fibers into a contact lens.
 2. Themethod of claim 1 further comprising the step of applying a secondcross-linking treatment to the mat of polymer fibers after theapplication of the polymer coating.
 3. A method for forming a contactlens comprising the steps of: preparing electrospun fibers;incorporating the electrospun fibers into a contact lens; wherein thestep of preparing the electrospun fibers further comprises the steps of:electrospinning a mat of polymer fibers; and grinding the mat of polymerfibers to form a plurality of fiber particles.
 4. A method of forming acontact lens comprising the steps of: a. providing a polymer solution;b. processing the polymer solution to form a mat of fibers; and c.incorporating the fibers from the mat into a contact lens; wherein thepolymer solution comprises a polymer, a surfactant and a solvent; andwherein the step of processing the polymer solution to form a mat offibers further comprises: Electrospinning the polymer solution to form amat of fibers; Applying a first cross-linking treatment to the mat offibers; and Applying a polymer coating to the mat of fibers.
 5. Themethod of claim 4 further comprising the step of applying a secondcross-linking treatment to the mat of fibers.
 6. A contact lenscomprising electrospun fibers incorporated into a polymer lens; whereinthe electrospun fibers are prepared by electrospinning a polymersolution into a mat of fibers, applying a first cross-linking treatmentto the mat of fibers, and applying a polymer coating to the mat offibers.
 7. The contact lens of claim 6 wherein a second cross-linkingtreatment is applied to the mat of fibers.